Use of c-Jun or c-Jun activating agents such as UV or c-Jun N-terminal kinases (JNKs) for treating cancer

Abstract

The invention concerns the increased stabilization and activation of p73, a homologue of p53. Specifically, the inventors have determined that c-Jun, a component of the AP-1 family of transcription factors, is necessary for stabilization and activation of p73. Thus, there is provided a mechanism for initiating an apoptotic pathway involving c-June and p73 which can be exploited to combat cancers, particularly those lacking a functional p53.

1. A method of screening for substances that are capable of mimicking the activity of c-Jun in stabilizing or activating p73, said method comprising:
 a) contacting a first reaction medium comprising a c-Jun −/−  cell capable of expressing p73 said cell comprising a nucleic acid construct comprising a p73 binding site linked to a reporter gene, 
 b) determining and comparing reporter gene expression level in a comparable second reaction medium untreated with the test substance, a test substances which alters reporter gene expression levels in the cells of step a) compared to the cells in step b) being identified as a stabilizer or activator of p73. 
 
     
     
       2. A method according to  claim 1  wherein stabilizing or activating p73 comprises:
 i) increasing the halflife of p73; 
 ii) potentiating p73 transcriptional activity; 
 iii) activating p73 to induce cell cycle arrest; and/or 
 iv) activating p73 mediated apoptosis. 
 
     
     
       3. A method according to  claim 1  wherein the cell is also JNK −/− . 
     
     
       4. A method according to  claim 3  wherein the cell is JNK1 −/−  and JNK2 −/− . 
     
     
       5. A method according to  claim 1  wherein the reporter gene is luciferase gene or green fluorescent protein gene. 
     
     
       6. A method according to  claim 1  comprising a further step of preparing a pharmaceutical composition comprising the test substance. 
     
     
       7. A method according to  claim 3  wherein the reporter gene is luciferase gene or green fluorescent protein gene. 
     
     
       8. A method according to  claim 4  wherein the reporter gene is luciferase gene or green fluorescent protein gene. 
     
     
       9. A method according to  claim 1  comprising a further step of preparing a pharmaceutical composition comprising the test substance. 
     
     
       10. A method according to  claim 3  comprising a further step of preparing a pharmaceutical composition comprising the test substance. 
     
     
       11. A method according to  claim 4  comprising a further step of preparing a pharmaceutical composition comprising the test substance.